Patent GB-1085073-A (GB)
Title: Substituted quinolizines and preparation thereof
IPC: C07D215/227
Filed: 1963-12-31
Abstract: The invention comprises novel compounds of formulae <FORM:1085073/C2/1> <FORM:1085073/C2/2> <FORM:1085073/C2/3> <FORM:1085073/C2/4> <FORM:1085073/C2/5> <FORM:1085073/C2/6> <FORM:1085073/C2/7> <FORM:1085073/C2/8> <FORM:1085073/C2/9> <FORM:1085073/C <FORM:1085073/C2/122> <FORM:1085073/C2/133> wherein R1 and R2 represent hydrogen, hydroxy or lower alkoxy, R3 represents hydrogen or lower alkyl, R4 represents hydrogen, lower alkyl, alkoxy, alkenyl or alkynyl, R5 represents hydrogen, hydroxy, carboxylic acyloxy, alkoxy, -COCH3, -COCH2OH, -COOH, -COOR11, where R11 is lower alkyl, -COCl, or -CONR6R7, where each of R6 and R7 is hydrogen or lower alkyl, or R6 and R7 together with the nitrogen atom to which they are attached form a heterocyclic ring, or R4 and R5 together with the carbon atom to which they are attached form a keto or cyclic ketal group, and Z is an anion, and the non-toxic, pharmaceutically acceptable acid addition salts of the free bases.  The compounds may be prepared by refluxing a compound of formula <FORM:1085073/C2/144> with a slight excess of an acid condensing agent to obtain a compound of Formula II or VIII which may then, if desired, be reduced to give compounds of Formula I or VII.  Compounds of Formula IV or X may be produced by cyclization of the corresponding compounds in which the D ring is unsaturated; these compounds may also be reduced.  Reduction of the double bond in ring D also results in the reduction of any keto group present (compounds in which R4 and R5 together with the carbon atom to which they are attached form a keto group) to a -CHOH group.  The keto group may be regenerated by treating the corresponding alcohol with chromic anhydride in acetone. The keto group may be protected by conversion to a cyclic ketal group by treating the keto compound with ethylene glycol in the presence of an acid catalyst.  The hydroxy group may be protected by conversion to an acyloxy group, the hydroxy group being restored by boiling with a strong mineral acid.  The cyclization of a compound in which R5 represents a carboxy group using phosphorus oxychloride as condensing agent results in a product in which R5 is -COCl.  This acid chloride may serve as intermediate in the preparation of many derivatives such as esters, amides, ketones, anhydrides, amines and alcohols. Compounds of Formulae I and VII may be prepared by catalytic hydrogenation of the corresponding compounds in which the C and D rings are not fully saturated.  The quaternary nitrogen atoms in compounds III, IV, V, VIII, IX and X can be reduced to tertiary nitrogen atoms by catalytic hydrogenation.  Compounds II, III, IV, V, VIII, IX, X and XI on treatment with alkali undergo a shift of the azomethine double bond.  Treatment of compound II for example will result in the formation of compound XIII. Compounds of Formula I or VII in which R4 is hydrogen and R5 is -COCH3 may be prepared by reacting the corresponding compound in which R5 is -COOH with methyl lithium in an anhydrous solvent followed by hydrolysis. Compounds in which R1 and R2 are lower alkoxy can be dealkylated employing hydrobromic or hydroiodic acids.